Viewpoint

Ubiquitination for Activation: New Directions in the NF-κB Roadmap

Signal transduction through the T cell receptor (TCR) and a costimulatory molecule, CD28, results in the stimulation of multiple
signaling pathways, leading to the activation of several transcription factors including activator protein–1 (AP-1), nuclear
factor of activated T cells (NF-AT), and nuclear factor kappa B (NF-κB). The molecular mechanisms by which NF-κB is activated
by TCR–CD28 have only recently become known. New findings indicate that the adaptor molecules CARMA1 and Bcl10 are essential
to the process. Additionally, a critical role for MALT1/paracaspase has been identified. MALT1, CARMA1, and Bcl10 form a tripartite
protein complex, in which Bcl10 is thought to facilitate the oligomerization of MALT1 monomers. Overexpression of MALT1, as
observed in a subset of lymphoma patients, leads to the potent activation of NF-κB, suggesting that MALT1 might stimulate
(directly or indirectly) the kinase complex [IKK, inhibitor of NF-κB (IκB) kinase] responsible for activating cytoplasmic
NF-κB for translocation into the nucleus. Moreover, the MALT1–CARMA1–Bcl10 complex is responsible for ubiquitination of NEMO,
a step that appears to be critical for TCR-induced NF-κB activation but not for induction mediated by other stimuli such as
TNF or IL-1.

Reviews

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Samuel H. Wilson and

Kenneth Olden

The Environmental Genome Project: Phase I and Beyond

The National Institute of Environmental Health Sciences (NIEHS) is directing a bold initiative to assess the ways that genetic
polymorphisms may influence individual susceptibility to environmental insults. Hundreds of genes have been selected as candidate
determinants of morbidity, and sequence analyses, along with functional studies, are revealing how various polymorphisms affect
human health. The genetic categorization of factors that regulate the interactions between the individual and the environment
involves diverse biochemical and epidemiological approaches, technological and clinical advances, as well as ethical considerations.
A vast database of genetic polymorphisms has already been compiled and will be expanded as the project proceeds.

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Reginald F. Frye

Probing the World of Cytochrome P450 Enzymes

The cytochrome P450 (CYP) enzyme family catalyzes the oxidative metabolism of numerous endogenous and foreign biotics and
thus determines individual responsiveness to drugs. The clinical relevance of factors that influence CYP-mediated metabolism
can be estimated through the in vivo use of “probe drugs” that are exclusively metabolized by an individual CYP enzyme. A
cocktail strategy, in which selective combinations of probe drugs are used, can reduce the time and cost of clinical investigations
into drug efficacy and interindividual variability in responsiveness. Significantly, this approach minimizes intraindividual
variability by allowing a comprehensive evaluation to occur in a single day.

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Ryan A. Adams,

Melissa Passino,

Benjamin D. Sachs,

Tal Nuriel,

and Katerina Akassoglou

Fibrin Mechanisms and Functions in Nervous System Pathology

Beyond their function as conduits for nutrient delivery throughout the brain, the cerebral vasculature provides guidance cues
for axons during neurogenesis. In several brain pathologies, rupture of the vasculature allows blood proteins to enter the
brain with subsequent edema and neuronal damage. Fibrin is an example of a blood-derived protein that accumulates in the brain
after vascular disruption. The role of fibrin in human neuropathology, elucidated in part through animal models, is thus extended
from that of a blood-clotting protein to that of a component of the perivascular extracellular matrix that regulates inflammatory
and regenerative responses in the central nervous system.

Net Results

Sites of interest on the World Wide Web–edited by Rick Neubig and David Roman